Document X87pMej2rBxEZ9M9EEJrxxV5g

~~SRICA~ PE~RO~EU~ lNSTITlTE ledicin -and diclo)ic:>l .S:::1ence [:epartment Tccicol?gy Committee I an~ let Hotel fan Liege, California Wedn~sday, January 11, 1984 9:00a.m. : TT NDArJCE: J. A. MacGregor. Ph.D~- Chairman P. fl. Craig, V.M.D. - Vice Chairman < omrnittee Members FI:'esent \:.D. .C. ' R~ .M. ! - J . A. ~ < r~: L ~~ Broddle CJnavay Clark CJomes G ~ rv in H:~lder K:Jna L1kin L"'"' i ;s R.W. A.E. R.N. C. AM.B. F.B . W.C. c.o. Mast Mekitarian Hoth ~;chreiner f> lomka ":'homas ':'homas War_d ''th<>rs ?r~e.sent ;_c Blum ' .-;ol berg H.N. MacFarland S. S. Sternberg :;taff Present ~- Blank .; T. Cragg K.A. Hazer C.E. Holdaloforth OPENING REMARKS Chairman J .A. MacGregor opened the meeting by welcoming those present, including the SPAR consultants, Drs. Leon Golberg and -steven Sternberg. She ad_vised that annual t=roject proposal sheets_ for ~1985 woul"<l 'be sent soon from staff and that the member.~ should gfve careful consideration to- pricr:iti-zing the project5. In order that the BP QB691 BP-00012101 pr-ocess run :>mootl;ly, Dr Mac';reqoc- fur-ther reccmmenoed tt1at .,-ach company':; HES( r-pre~e'ltative be closely 1nvolved J r .;~ t 1 e a s t -~ 1 v i s ~ :j o! t he i c- :om p~ r y' s p t" i or 1 t i z a t i on . This would help insure the successful implementation of the ll35 toxicoloqy program. In order to help the memb~rs pr1oritile the 1985 projects, HF.:SC l.l'ant~- .; :)alance of 3 -reas of testing. These include: l) issues (e.g saacline, benzene"); 2_) methods development: and: 3) basi: inform<>tion. Dr. ~oldsworth added that it is not too late to subm:t rPsearch proposals for consideration in the 1985 budget. The Toxjcology budget is $,.8 million for 1984 and the task forces at"e urged to move their projects along now in order to avoid a year-end rus~ to c~mm~t budgets. All but a small fraction of .the 1'4 83 budget of $2.4 million was committed last year. Thig included PS-3 money which HESC would not a llov ex~Cended w1ile they ~Jere reviewing proposed etudies .Jnder- this pro:,ec::. This and synfuels money vas therefore all o"'ed tc be ca :-ried-over. ! 1. SPECIAL REPORTS A. Coordinating Cornmittee_on Gasoline {CCG) Dr. Slomka reported that the OH-39 task force had v1sited Dr:-. Cur-tis Wilson of Scripps Institute just a few days previously. This investigato-r will help the task force evaluate -a por:-u lation of gasoline abusersf o r immun~logical effe~ts. On behalf of the CCG, Dr. Slomka requeste.d information updates from -a-ll tox1colo-:;~y task forces on gasoline. There i.B a trend toward me-re coordinating committees and Or. Slomka recommended that more technically orienced ind-ividuals be appointed to them in the future-. Discussion turned to recently completed and ongoing toxicological research with. gasoline. The proceedings_ of the Boston nephropathy workshop have been publishedby API and will be peer-reviewed for subsequent publication in hardbound copy in the Advances in Toxicology. The UAREP report is nearing finalization and should b~ available soon. BP 08698 BP-00012102 It "a.3 d.:cided that. i1t:er:ur. reports 1.1ill be obtained from th"' ..:ontractor regaralrtg r.he PS-53 "time-course" qavage stcrly. The fin~l r~port is expectRd midyear. 8 . aenzen~ P.J. GarvJn ~eparted or the ~tatus of talks between the union ana industry on l benzene standard. This activit:~ 1s being sponsorec: by OSHA which is scheduled to issues th-;. standard ir. June of this year. Mr. Garvin saicl that, thus far, talks have focused on ancillar-y issue, steering away from a PEL. Regarding EPA activiti~s, th~ proposed benzene standard tor rnalei-; anhydride plants has been withdrawn under stationary sources r-egulation. However a standard is expected fo.r. coke pla:-tt:s ar-d a NE:SHAP for refineries will be forthcoming. ~obil ~ources may be regulated in the futur,o . .a. C.'1A .sp.:nsor-e::'l-epJ.denioloc;:y stucty has recently been completed, C.O. Ward reported. The results are equivocal and depend upon which control group is used fo~ comr:a rison. A cohoct of c:oncuccent controLs was very heal thy ..,. i th 110 inc id-~nce c.f leukemia, far be low the nationaL .:lVe~a-:;e. :::orr.parison to this group sho..,ed an excessive cat~ of leilk:emi~ in the exposed vorlcers, which whEn compared t) the national average appeared c o n v e r:- s e l y , t o h a v e-- :1 or:- rna 1 i n c i de n c e r a t e s o-f- t h i s di~eas~. Cu~~ously, no ~Ases of acute myelogenous leul<:emia QCcurced in tr1e expQsed wor-k:ers. C. Aspha1 t I".B. Thomas related thitt IAR<: would complete its review of asphalt (bitumens) oy th~ end of February. API has been i-:'l-vi ted to send one participant in the review proceedings (not yet chosen). Barry Simpson of Shell International "'ill par-ticipate on behalf of CONCAWE while Ted Chipperfielj, consultant retiree from IP wi 11 provide chemistry expertise to the IARC review panel- The <isphalt consorti-t:m of trade associations is reviewing a rinalized draft of 2 monographs dealing with asphalt (one .:;~-:t chemi..stry and another on biological effects). Further revisions will be-sought, Or. T llamas ad.'ied. BP 08699 BP-00012103 -4 - The ccnso:tium is al;;o conau-:ting <~ feasibility evr.~lua ti<'n for a po~sibl< e!)idell!ology study, W.D. o!:'oddle saio.::. ; i)r. Chaizz" cf Ge-:>r-getown Univet:sit'{ !'Jas tleen contrr..cte-:l to "erfcc-m the teasibllity analysis. Dr. aroJdle also updated the ~ommitt:ee on the status oE t~e NCOSR sponsored skin-painting studies which are to be conducted at A.D. L ttle. Regac-.:Jing the A.D. .ittle st.udy, samples ace no\J being prepat:"ed and the pr.ot,col '?enerated. The study l.l-ill encompass 50 g-coups ~xposed to variously generated asphalt and subfract iorrs thereof. :hemical analysis ..may be done directly by NIOSH. NIOSH ;..oill sponsoc a symposium, Dr-. Broddle continue~, which is intended to gene!:'ate guidelines for tiological monitor~ng. I t can be concluded from all this tU::JSH acttvity that asphalt is oi hi'3'h c:-oncern. ~urthermore, sJbstantial litigation agalnst the industcy is o<:curring wher-e worker-s are claiming to have suff!red health effects from asphalt exposure. D. Hvdrocar-bons (Gasol.!._nel in Gt:'oundwater Dr-. F.B. Thomas l':'e!ated that -MBSD had initially reque3ted as3istam::e in identifying which chemicals might be present (a,d :;.n what concentrations) i.n g 'oundwa ter contaminated ty gasoline and other hydro- carbons. From this rt?quest, a multidisciplinary group was formed under EAD ,..hich is ev-!luating the solubil- ities at different temperatures of those chemicals likely to be pres~nt. Company records reveal that benzene, toluene, xylenes. roethyl tertiary-butyl ether, tertiary-butyl alcono: and ~thyltolQene are prese~t at con:::entrations and ir pc:>poctions which depend upon their water sol'ubi]it., the distance from the contami- nation- and a variety of other :'actors. Dr. T-homas added tha.t MBSD i-.:3 currently acting in an a-dvisory capacity but may beco~e mor~ ac~ive later if testing is needed. TRC has beer cont t:"ac ted to conduct. a 1 i tera- ture survey on the potential health-effects of c.ontami- na ted groundwater and may perform experiments to model the plume of a gascli'le spill. l>,side from the obvious question of ocal ingt':stion of contaminated water, Dr. Thomas n::.ted that 50ine of the issues Yhich ace being e11aluated include: 1) whether food can be washed with contaminated watec: 2) -whet.her sJch water can be use-d 3:for bathing and: whether ooiling increases or reduces c:on tam ina n t c.:-.. ncen tra t ions. Dr. MacGreg-o-r added that. i t is mo~t impcctant that t.he in-terdisciplinary B_P 08700 BP-00012104 qrou!' n-.Jt tall n~t-:i1d sched1le in light of the importanc~ cf th<7 .:ontami1atej ;..;r.tter issue r.tnj oecause rc:3t;iole tutur., :'-lP.-2[) healt t:elated re.'5eat:ch hioge-'0 upon t~E concluR1on reached ny the group. Dr. ~acGt:qgot: s~id t~at the 1oxicology Committee should be ready \..'hen t!1is gcoup deflnes '.lh"'t to test by having t:ox stu~i-?s id"ntif:ed and protoc0ls <3enerated t)y the tim.;; :;ample::~ become a.ailable. Cr. Thomas will poll Tcxicol-vg, Sut:-commi':t~e chairs tc compile "~ Jl.st of needed Etudies. E. TSCA Section 4 Activities API has formed a group in response to EPA's new pro- gram: Leaking Undergro.md Storage Tanks (LUST), which is -~tte>mpting to evaluate the extent of undel:'ground stot:a<;e t.:~nk l-~aks anc assor::iated pt'oblems, R.N. Roth l:'epcrted. EPA is presently evalu.~ting the ability of the industry tc comply wit.h a range of standards vhich it is considering. F'inal1zed <;LP's have !>een issued by EPA in Vol. 48, p a '3 e 53 9 4 E. of the Feder a 1 Reg is t e r , Dr . MacGregor not~d. It is possible to submit comments on these standar-ds annually. F'. K. Hoover (API/MBSD staff) lS coordinating the fir,lt ronnd of responses .fot' the industry and those interested should submit their comments to h~r. Dr. Mac:]regor said that the new guidelines call for detailed chemical analysis of test samples e\en foC' acut-e tests. Even while. responding to some. ,,f t.he items which appear unreasonable, it was agreeo thi\t !!.PI wouli try to comply w-ith the new guideLines in Eutur~ toxicity te:lting. In a t'elated area, SPV~r.':ll members ncte.J that their studies had been au-dited b',' EPA, either in :heir own laboratories or 1n a ccntractor:-' a. EPA seems to be steppin'3" up its activities in this area and has bPcome more sophisticated in the auditLng process. The Inter~gency Testinc Committee IITC) recently issued a list of 82 chemicals and API/HSRD will supply orcomment. OleolaminP i3 on the list and is interest to the industry becau.!;e of it-s presence in lube oils. Drs. Craig and Daikin -recently made a presentation to the ITC to argue against testing individual component:~ of complex mixtures in order to pt"edict the toxicity o the whol~- The presentation seemed to be well ceceived. BP 08701 BP-00012105 - 6 - Dr. Poth C'~latN'J that API/ liSHD nas ma,je comment to EP.!\' s prc;><)SAd test ru e on ?thyltoluene (0:1') and tci- meth~l~n,?E:n~ ~TMBi. A;>! h'ls argued that r.:P"- shoul<1 n c t h ) l d t h <! : e t C' o l e L m i n d us try l i 'll b 1 ~ f c r t P. s t i n ~ these C)m~.>cund~ on the basi;<; that they occur tQ a few pe::-cent iCI gasoline (.;nd because gr:-eat qu"'ntities o! ga,-;oline 'lre sold, th,:. pe1:r:Jleum industry thus indi- re::tly becomes the lar-gest pC'oducer of these chemi- cals). I>.PI has also u~gued (similar to the I'l'C: pre- sent.:tticnl. th.~t inciividual tox testing results fr-om these t"'o compQunc.s w: 11 net be lseful in predicting the toxicity of gasoline which is comprised of at least 300 chemicals. It is estimated that perhaps one year rna y pass before EPA. m-ikes a decision on this issue. Therefore, the ~oxicnlogy Committee may not be asked to perfor-m studies foC' this length of time (or ever-) on ET. TK~ or even a C-9 cut w~1ch EPA might be willing to substitute as mo~e C'epresentative of gasoline. Specif- ically regarding C-9 cuts, the Inte~agency Testing Cbmmittee has r~comm@nded t~ EPA that additional toxic- olocy infoC'mation ~s need;.;. M.B. Slomka indicated that :::uts "ith hic;h l~vel~1 of C-~ ar-oma-tic compound.s hav.;. long been usej ir great quantity as vehicles for pes-ric ices_ EE'A has al:so oecorne 1ntere.sted in cresola, Dr. R.W. Mast rel.:.ted. Because cresols occur in gasoline, another test rule may te issued affecting the petroleum industry on the same basis as that for ET and TMB. Dr. Mast noted that an int:erind<Jstr.y "Cresols" task force exists which was negor:iating with EPA o.n- a voluntar-y testing pr-ogram. Negotiations have broken down although some of the tas-<: force members ar-e still trying to obtain fu_nding. rr. Bt:oddle added that several genetic t:JJC studies h.1ve been ccmpleted on an equal m i x t u r- e : f o , m a n d --P- c r e s o 1 s , s om e o f w h i c b 1o1 e r- e positive. F. Methyl tertiary-Butyl Ether Dr. Conaway provided a written summary of this project as 1o1ell as an oral presentation (Attachment :r;)_ The participant:s in the:~e studies are considering whether to perform pharmacokinE-tic studies with remaining fu.nd5 of S28,000. Dr. Curti~ Klaassen and an inve-Stigator- at Naylor-Dana Instit:ute are being considet:'ed for- these studies. Dr. Golberq men-tioned that Dr. Cal-dwell of St. Mary's Hospital in Lon~on is also highly qualified to perform such resear<h. BP 08702 BP-00012106 I) r. ~ r '3 1 'l lntroduc-~d tb~ rese3rch re.:Jor-t por-tion of the m.:>~tin<J, asking task fo~ce chairs from Physiological R .~.sponses tc le<~d cff. A. ~iclogical Response~ 1. PS-23: ImmuQology Repo.rting foe- J. BLtala, Dr. Br:oddle 1ndicated that r:esear.ch i::: currently underway to assess possible aifferences in immunological effects of carcino- genic and nonca["~inogenic polynuclear aromatic hydrocarbons. T~i~ research is taking place in the laboratory of Dr. Albert Munson of the Medical Ccllece of Virginia. Benzo(a)pyrene and benzo(e)- pyrene are th-e moiel ?NA's used and differences betwe~n these compounds have been observed in a nt.:mber- cE immunol,:gical parameters when injected intraperitoneally into B6C3Fl mice. Multiple immunclogical test~, are being validated during the o fcours~ t~is r~sarch. The T.;sk Force is .Jlanning to assess the effect of hydroca~bons on th~ immunological defense system of test ~nimals by de~e~mining whether such chemicals alte~ the response to a viral or bacterial insult. Dr. Brcddl.e added HaP and BeP will be used in this effort as well. 2. PS-29: Neur~toxico1~ The task fo~ce is currently following-up on reports that prolonged exposure to high concentrations of toluene may be ototoxic. Using the auditory evoked response paradigm, resea~chers a~ SRI have observed a hearing d-ecrimen~ in the high frequency range of rats exposed to vapors of toluene at 1000 ppm 14 hou~ -per day 1 7 days per: week 1 for 5 weeks. SRI belie.res that cochlear damage may account fo~ the otservations. Because of these studies and because of allegations that toluene may account for CNS damage in human solvent abuserB, the task force - BP 08703 BP-00012107 - f; - 3sked ;:eter S!=erce:- of ;.:instetn to cut .~oditioniil :\1.3 t t :.lsues Eror-; the ;::r>viousl y conoucted tolt.:en~ n.;,urotolCici ty srud'/ to <ieterrnine whether- lesions ~er-~'< leto:!ctable i11 nuclei or- neural tr;;tcts asso::iater. ~o~ith heartnJ T.is ha:; been completo;!d and res::l;s wer:e ne.-:at.ve. ;:;instein has been ::~sked to expani the fin.;! report 'Jhich was very Dt:ief. si nee the cochlea of cats from the toluene study wer~ not 5-'l.Ved, it '"'ill not be possible to deter-min'" ..1hether a sp~cific effect in this organ has cccurr-ed. Thus, ~ut:t~er- studies may have tc be under-taken to ans'-'er: this critical question. The task force '"'ill visit s:u to evaluat.e their results and consider pcssitle futur-e research. 3. PS-32: Percutaneous Absorption Mr. Gat:vin noted that r<esearch is being conducted witn 3 1nvesti.:;ators including Drs. I.H. Blank (!"ass :;en. Hospitil, 'iarvar-d), T.J. Franz (0 of Washington) and 1l.1. Maihach (l'. California). Or. Blank has measu:e<'! the flux (ul/cm2/hr-) t.hrough human cadaver strac~m ~or-neum of benzene liquid in various vehicles and as a vapor in air. Benzene vapor in air pen~tratPs as well as the liquid, ei t~er in pure form or Ln a solve.nt vehicle. The task ~orce will Vi3it Dr. Blank in early Februar-y. Dr. Franz is also study~ng the skin absorption of benzene, report in<J re-sults as the percent of benzene absorbed. ~his 1nvestigator is inactive at this time regard in 1 APT research- Dr. Maibach has ccmpl~ted phase 1 ~hich concerns method development and background det~rmination of benzene in humans. Ho..,ever, t1e is stil-l attempting to initiat.e his stud!eS on 13-C henz~ne in humans. Mr. Garvin noted the conclusions stated in attachment from t.he work of all three :nvestigators on benzene. Dr. John Kao of 06k Ridge National Laboratory has recently received an API grant of $100,000 to st.udy the percutaneous metabol i-sm of 1-2 ring aroma tics, including benzene, and the efl:ect of thi.s met.abolis~ upon dbsorption. C-14 labelled benzene '"'ill be studied in tn~skin of micP. and other mammalian speciea, possibly ~ncl~ding humans. BP 08704 BP-00012108 :n th;; r:-ecent pa;t, c:assic.3l neur:-otoxins '"''er:-~ E-lnplo:d to prcdu'e discrete lesions (rather than ~~n~r~lized CNS e~fects' in a , attemot to v~li~4te J beh,lvior;~l t~.>t~ (incl,Jding open fLeld activitv) ;- 1J r : h e i r:- s e n $ i t i v i t '( . o r:- . T"' a s t r e 1 a t e .1 t h ~ t hsid-"'> cpen field, the n:!rnaining twc te~ts inclu:l.;-d, avoi~ar:e-r-e.sponse (shuttle bcx) 3nd c:Jnsu!f1,;tory beh3v:or. The open field test could rlistinguish treated Erom untr:-eated animals ~t a dose level whi:h was not detectable histopatho- logic~lly two weeks after administration of a ;<;~~ngl"' i.p. dose (high dose: 2 mg/kg). Lab .... ark h;1s Deen completed, rlraft re'ports issued and reviewed, and the contr~ctor is revising the final r~port. No further in\estig.c tions are planned at tt1 is t: i me. A tutorial may ~e ccnducted for HESC on the possi!'lle nt>ed for" neuro/behavioral testing by API. Dr. Scala i5 com~ilin~ a l i 8 t of candidate pres=rters who are ecpert~ in ttlis area and are out- si6e the industry. There is 3lso some interest in :::on::h:::ting an API-spon:"ored, 2-day ~o~orkshcp after:thE' HESC tutor~al, for industry scien.tists interested in the field. Finally, Dr:-. Lewis noted that the Grasso ::eporT: on t.he human behavior-al effects of ligh~ h{drocarbons is being reviewed. A critJque of animel studies may be added to this predominantly cl ir.ical revie~. 5. ?S-54: Human Bone ~arro~ Test Validation Dr. ":'homas report~d th.~ t work is proceeding w i t.h Dr . .J.H. Jandl cf Harvard ~ho is attempting to dev~lop a human bone marro~ culture sys-tem in which benzene and other hydrocarbon~ can be quantitatively introduced and their effect measure. This syst~m has the potenti~l to provide, in the case of ben-zene, direct information on the actual target orgar. affected in humans. Dr. Jandl will employ a Dexter medium in which a feeder cell layer is first establishe1 to pr0vide the necessary microenvironment fat' che t-ont- marrow precursor- cells. A"fter exposure t~o the tE>s t ma t.er ial. i t is hoped that the system will be anle ':C measure such endpoints as stem cell proli:erating abllity and stem cell viab'i]ity, among other~. Dr:. Jandl is cu.rC"ently BP oB705 BP-00012109 - }0 - ouild:n3 hlS apr;aritus "nd ~stablishing growth of the cqlls in t~~ lexter m@dium. ~he task force h o !J ~ s to v i s i t :l L ,J -'1 rr ri l by .: h ~ end of the f i r s t qu,'lrt.-r of 1984, ::hcpendirtg upon his progress. Thi:;. project is no; in the final stages, Dr. l-Iard rP-lOJt.ed. A fina: repcrt has been issued <.Thic.h addresses thost' t.~chni,:al and quality assurance comments w~ich tte IRDC principal investigator deemed appropriate Reasons for not incorporating otht-r commPn-ts ha'l;e been addressed in a separate letter:- f;:--om !Roc:. The final report has been sent to the senior Toxi<ology Committee member from each participating ccmp1ny. Dr. Ward added that Dr. H. N. Macfarland ha~ subm:tted a manuscript to the Ameri~an CcllegP cf Toxicology so that the results of t!e s-t>.Jdy ma. app,ar i?'l the peer-reviewed 1 i tera ture. 2. E..S-53: Motor Fue!.._:To.!c.ic..!c:::Y Individual chemicals are being administered to rats in 28-day gavage studi~e in an attempt to identify chemical types responsible for inducing the acute nephropathy which is hypothesized to pr~dispose male rats to renal carcinomas. Dr. Halder explained that the oral .rour:e h.:~.d previously been found to tnduc~ the same acute r~nal lesion found in .short- term inhalation exposur+?s. The chemicals t~ested are sn<Jwn :n Attachment II-1 and II-2 and r-esults are r"'ported in !1-3. n.s suspected, the br-anched alka!".es ar~ the must active. The study desi~gn is giver, in rr-4. C1rrently, a time course study is being conducted on unleaded gasoline to aaequately de-fine this para.,eter. (,U:-4/5). Next, several naphthas "'hich usually comprise gasoline and severa-l distillat.Lon cuts of gasoline will be tested in 90-day inhalation studies (II-6). R~garding CIIT studies- in ad~ition to Dr. Bus' work: on metabolism a.nd mechanisms of male rat nephropathy, Drs. :;wenberg and Butterworth are co-Rsidering ini tia tion.Lpromotion and mutagenesis tests. r.espectively-. Information will be transmit ted on a re9ular oasis to a previously designated API/Tox-liai!Jon group (Cra.ig, Halder, BP 08706 BP-00012110 - 11 - l'clus;.ccth, Le~is ~PI/QA progr.~ss of the ..{OIk on .; i te. will monitoc- Tre activities cf :his task force are summarized in ;.tte~chment III--1. Dr. \~e~cd 3dded that the task force is current}' cons leering extending preliminary wock o~ Dr. Raymond T1ce of Brookhaven. Dr. '1' ice has r:esta i n.;d blood smears from the 5-da-y benzene inhalaci0n pilot study to evafuate the incidence of micronuclei in the 2000 ppm and 0 ppm groups. This effort was successful. Now that the technique :.s valicated, the task force may extend Dr. Tice's work tc the 90-day study. In addition. the task force is evaluating another proposal from a Ercclchaven researc-her: Dr. Eug-ene Cronkite. Dr-. Cronkite proposes to implant a diffusion chamber containi_ng bone marrow into a host mouse which can tnen ~e exposed tc benzene. The technique has the pot~n:.1al to us" :uma-n !:>one ITarrow. Fin-ally, the t-'<sk : orce is r-e-ealuat lng the-v.alue of cenducting a low~dose chron~c benzene study (inhalation). 4. P:".-22 _: Coke To;o ci:_y The Ln-life port:on cf a 2-year study on ~icro n i zec, delayed pr<.cess coke has been completed in rats and monkeys (Attachmen~ IV-1). Dr. Halder added that results (limited histo for rats and only in-l1fe fnr mcnkys) ,~re available through -13mQnths and a draft final report is expected soon which will inccrp,rate the remainder of the study (r-Y-213). A p:rev.ous in-life observation of ribca-ge "flaring" -i-n monkeys has now been disco.unted by experts from the Primate Research Institute. P t"evious mutagenesis- and dermal carcinogenesis results are summarized in Attachment IV-4. 5. PS-45: Refinery St~eams Toxicolsy Dr. Ward related that acute and subchronic toxicology studies ar~ performed on generic refinery streams in this ptojecr. The results thus far are reported in Attachment '1-1 w--hile current resear-ch activities are outlined in V-2. BP-00012111 - 12 - Jnd~r this proj~ct. t~e suochronic toxicity of raw and s-lect"'d level; of hydrotre<tted sh.-:112 oil "'ill tt' ch.'!.racterized in 26-day rat der:-mal studi-=s, (~ttachment ~I-1). A hiYh nitrogen crude will also te te'lted for c:omparati.;e purposes. 'J'he samples hav~ ~~en prepared and the taEk force has selected Sprin~born Researct Inst~tute to conduct the t@sts. The final report, on tte xylene reproduction/teratology study has been acceptec. The only treatment related effect was matet"nal to,icity at the 500 ppm level. The final t'eport will be s~omitted under TSCA section 4. The two ceneration in'1alation reproduction/teratology study on toluene began Octoher 31, 1984 at IRDC. The study des1gn is ~ssentially similar to a 1 generation study, f!Xc:ept that it is extended to 2 generations. 1'he exroE11re levels are 100, 500, and 2800 ppm. The study is being :onduct<'-d in iieu o~ TSCA section 4 test rule. Th.-re have be~n some problems with the hourly IRreadings ;oc- the contr<:l chamber--they are routinely in the lo,. r:-~:m range (1-:o ppm) with occasional peaks at 4C pprr. rn order to v.,rify (:hamber: concentrati-on::~, the cha~coal tube sampleR wer~ obtained in the control chamber::~ o:JVet: a t'..rO wee~ pericd, and analyzed by Clayton Environmental Ccnsultants using a NIOSH approved method. This-analy3is shJ~Jed tha.t the toluene cQn~entr~tion in the con~rol chamber was below the limit of detection. .009 ppm. Cur-r-ently, charcoal tube samples are being taken in the exposure chambers over "'thr-~~ days. Saul Blum has alceady visited IRDC to exa-mine their analytical systell', and he will also examine the daiiy JR measarement_a, the -cbaccoal tube sampling. and other ~tudy data being obtained from IRDC. The Task Force will consider:- Dr. Blum's evaluation, and the charco~! tuhe data, when they decide . whether ''r not to contin,Je the study--this decision will be made prior tn mati.ng whtch is scheduled for January lB. API staff will brief HSRD on the status of the study in an eff-:>rt to g.,t_ g-uidance on possible EPI!. discussio'ls. Toluene-induced audi tor:-y e-ttects have been reported inthe literature. The Task Force plans to evaluate addin9 auditory studie-J to th-e protocol P. Craig BP 08708 BP-00012112 i3 - and SE''-'e:.il rnemt,er-s of the "'oxicology Ccmmittee stronqly recommended t~at ~uditO~) studies be done nut not in conJunction ,.;it, the presen: toluene study. The singl~ qenerati:>n repro:jucticn study ""ith hexane hc.s b~en ielayE>ci un:il the toluene study is prcceeding smocthly. Planning :or the gasol1ne reproduc:ion st~dy remains on hold while background info~mation is obtained from the Industrial Hygiene Committee, Environmental Affai~s Department's Groudwatec Task Force (Ben Thomas is the liaison), PS-32 Skin l>bsorption, and the Occupational Health CQmmittee. Le<:n Golberg will be asked to prepare l re-port on spe:ies select1on. Dr. Kuna will request f'rogress repQrts from the above groups at 2-month irtervals. The study plan p~-sentation to RESC is targeted for the th1rd quarter. D. Genetic Tc:xicol~ C. Schreiner presented ~n update on the status of tl1e refinery streams currently on test at Litton and ~ icrobiolog icid Associates. (Tabl!:! VI I.) Eight additional samples wi!l be sent to the contractors in 1~84. The work under PS-4 should be completed in 1984. The methods currently being valida.ted in PS-12 will become part of the standard mutagenesis batter~ beginning in 1985. 2. Methods Development (PS-~~) Ames Assay moditiClti-or.s are teing investigated at Microbiological l>.sEociates. The work to date has shown that increasing the concentration of rat S-9 and NADP yields an increased mutant response. Sever-al PS-8- samr:les ~o~hich had previously been negative, have now tes~ed positive in the presence of hiqher :oncentr.stions of S-9 and NADP. (Refer to Table VIII.) '!'he next set of studies includes the use of hamste~ s-~ a~tivation, and Tween 8D emulsions. C. Schreiner pret~ented the l\mes Assay Development w-ork from her labcratory. (Tables IX-XII.) They have also used hamster S-9 at 8-fold concentration BP 08709 BP-00012113 u- .]. n-:j 2 NI\DP in<:r<:C~St;>c:l mutant response. ~ioni l th~n c6mp,JtE'3 the :>tutation Index (slooe of the irliti.;l pe<rt'ion of th iose-respoose -:-urv-e) ln-:l <> C;~r::incg!OESlS :n.jex fr0m skin r:>~lntlr.q .::"85UlLs: I~ [ 1 A.ve. latency- No. animals w/tumor !." E N 1 --y;;g dose l X application fr-:!quency 10,000 Test materials are then ranked according to their M.I. <tnd C.I. D!:". Schreiner pre::~ented graphs ~crrelating the M.r. and c.r. rankings. For the middlP. and heavt' distillates, the correlation i.s 1uite good. with the exception of th~ C-4 ~romarics. Mobll uses ~n in-,ouae 100 SUS oil as i-ts pqsitivoP. control. lr. Schreiner recommended that API establish a repos1tory for reference materjals to te u~:ed as positive controls across the in.:lustr;. Or. Cc>naway r-epc-r-t~d that the f ina! repor-t on the liposcme delivery system for- cell transformation had been received last .J("ek. The major shor-t coming of the ~Jork ~Jas improper experimental design--too many parameters \/ere changed in each experiment. Due to limitations of time and money, these discrepancies were not corrected_ The investigator, Dr. Lando1ph, us:, o~ill submit a manuscript ~escrioing the wo~k to a peer reviewed journal. The rask Force plan~ to pursue additional liposome/cell tra~s~ormation studies ~Jhen funds become available. Vali.dation of .o;.everal assays i.s planned for 1984: 1) Sister Chromatij Exchange, 2) HGPRT mutation in CAO cells, a-nd 3) Unscheduled DNA Synthesis. Cat cracked clarified oil, c-5 aromat~cs, and ra~J shale oil will be used in these validat-i-on studies. When the validation studies are completed, the three assays ~ill become part of the standard mut-agenesis batt.ery for PS-4 p~sitiv~s. BP 08710 BP-00012114 ;s - l. Car=inooenic ?or:e-no:ia!. cC Crude Oil and ~is tiT~-- (?s-8~---- The 1'-'lsk F<)rce ha accepted t inal r?por:ts foe the Ph.asoo I (1976) ard Pha:;e II (1970) skin painting stud:es. Dr. >tEmmer's monograph on historic<J.l contr~ls ~as ~l~o be~n re~eived. Or. L~wis comm~nted ~pen ard t~an~ed Pod Anderson, API QA st:aff, for his effol:'ts in wcrking with Kettering t e c h r, i c a 1 s t a f : t-O i rn p r o v e I h e q u a 1 i t y o f t h e i r: wol:'':, recot'dke-epin~, anc1 healt:.h and safety a.spects of th< ~o~ol:'i.:: . Oak Ridge National L~borataries W~ibull curves on the PS-8 data. rloing the vork on a pro bono oasis, rigid delivery dat.,. are preparing Oak Ridge is so there is no Initi.~tion/Promoti>n Studies are no1.1 in their 70th w~ek. These interpretations can be drawn: C-2 and D-2 nsphtha& are w~ak promoters, and coca~cinogens, and :hey may counceract the effects of TPA in uniniti3ted ~nimals. C-2 and D-2 are not initiators. Tne Task Fo~ce de, ided to continue the I/P. studies t~ tn.;,ir ~:ull 2 tears in order" to- get the last ounce of value nd information from the study. D::-. Le-iilis f)lans to pr:esent the I/P study results at the Interne.tional ~kin Painting Symposium in F~dnce in .June. 'l'he chemical treat.ments project failed to receive approval from H8S(. The Task Force reviewed four alternatives and d~cided to close-out PS-8 with the end of the I/P studies, and to consider redesigning a chemical modificatiens p~oposal for consideration in 1985 under a new PS number. A final repor:~ on PS-8 will contaL"l an administrative summary {critical dates of co&tracts, study start ups, and ending dates, report-s received-)~ and a technical s mnma ry-. Gul! requested and rec~ived PS-8 samples to be used as p<>sitive contr:~ls in their t-oX- program. Gulf ~ill periodically update API on the status of these samples. - BP os71.l BP-00012115 - '6 - The T->sk !'"orce 11a,: hop<?d to )e able to correlate ct:emi-:al composition and biological activity, anrl had planned on uEing t1e ?S-24 report {Chemical Analysis of Het'rc::yclo:~ in Petroleum Crude Oil). However, this re~ort indicates that heterocycle analysis is extrem~ly difficult ~nd i standardized metho~ology directly applicabl~ to all oils was not developed. Some a~sistance for the chemical/biological t"elationshiF may be available in the soontc-he-released ~:o~~CAWE docum-e-nt .thich included potency rankings for 90 petroleum hydroca~oon materials. The effort to t1av~ Dr. John Weisburger prepare a monograph on tile tnterpt"etation and extrapGlation of ?.S-9 dat:a to predict occupational skin hazards has teen aoandonec. The task force will now turn its attention to the proposal by Trump and Lipsky. Drs. r:;olber.g and Sternl)erg will be asked to advise the Task force e-n th'? merits of the Trump and Lipsky proposal. The ~ask E"orce r as a.:cepted Kettering's final report of glcin painting studies of paraffinic and naphthenic base stocks. Tt1e T-3.sk Force has rec!ive-d a final repot"t Borriston Labs on thP. refinery streams paint1ng study which had to be abot"ted due to percent incidence cf mouse hep~titis virus. from skin a 95 The refinery stt"e.oms study has been moved to the Primate Resear:h In-stitute. A sentinel health screen lasting 4 .teeks was conducted berore the chronic animal_s vere orc1ered. This health screen sho...,ed that Jackson Lab mice h.ilve endemic Pneumonia Virue of Mice but i t -disappear::~ after 4 weeks at PRI. A pre_study conference held in November included a tour ot the facilities and th-e new air handling system. The 1900 skin painting animals were quaran-tined over the Eolidays. About 60 animals died betwen day 3-6 due to the stress of shipping from Maine to New Mexico. There has been ncr fu-rther mortalit:y. The study will b~in January 12, 1~34. Rod Anjerson, API QA, will conduct. an audit after the 2nd we-ek of tb.e study. BP 0871.2 BP-00012116 - l7 - Additional cefin~c' stre~ms will he t~sted in 1984. :'here dC curt:"e,tl, 8 samples "l.vailaole. The Tasl( Force wants to us~ a t l e a s t 2 diff~rent l~Doca torle'; for its pc>ject.E and J::J have ti1t! pcojects operacing concurr~ntly Bushy Run and H~zleton wee<> ''.uggested ty che T<;xicolcgy Committee rnembecs toe laboratories f(c the next set of studes. 3. Carci-!ogenic Poter!~::>f ~retreated Shale Oil and Distillates - SYN-8 Dr. Lew is l:"eported for l1r. Nees. The test samples for this skin pairting study are: a caw shale oil and 2 hydrotreated shale oils produced from it, a second raw shale cil and its daughter hydrotreated shale oil, and a 1igh nitrogen crude petroleum. Cistillate fractio1s sinilar to those in P.S-3 are being prepared new anc should be available in mid-l"e-bruary. Rattell~ Northwest Laos -was chosen as the laboratory ~ith Roger Renne as the principal invesrigatcr. '' rrestudy conference will be ~eld prior to the--initiation c:f the pilot study. In the pilot ::;tud.r, 2 di:~til-Iate.s each from the 5 whole oils ~ill ne painted at doses of 3X25 rng and 3Xl0 per we~k for 4 .o~eo:ks. 3attelle will be u.sing the C3H mouse Ecom Ch;1rlee River because the Charles River mice are Er~e of lung pathogens which are present in Jacksc, mic~. Battelle is currently free of endemic: :a.t:hogens and did not want -a-ny imported. Althoug, the Charles River C3H mouse is a different su~trcin of C3H mouse than the Jackson mouse, no impact or studv results and evaluation is a n t i c i pa.t eo V. OTHeR-BUS INES:;; suggestions 'for the summer meeting date ..and location were requested. Or. Lewi--s reminded the committee that the International Skin Paintin~ Symposium is scheduled for June 1'3-22 and that the Toxicology Forum is scheduled for the week of July 16. The summer meeting was therefore tentatively scheduled for the lst full week in July after the July 4th holiday. Washington, D.c., Denver, and Phoenix wer~ suggested as ~i~s. BP 08713 BP-00012117 - 18 - 'J. :LOS INC REMAI<KS .!I.~JD ALJJOURtiME'lT ''r. Mac-;rA9Jr:- trHni<ed API st-"f.f fc,r:- the:r ~ffocts in tanning and conducting th~ m~etings durJng the ldst fe~ :.;y.s. The qud.lity and fcXtent of rJLscussions_ and i-"<:Lsion-making dt the T.;s~ Por-e~ and fJll committee n~erings wee~ ~ery hiqh. ~he m~et1ng adjourned about 3:00 ~-m. Sut.mi ~ted by: - t.l~i~) 1\. - ;;, MacYG1ret.gtoLr<-~91t'F ~~airman tb~ icc l-ogy Committee P r f' pa ( e d by: l( ~: teven T. Cr-agg API Staff - """'Kathleen 'A. Hazer/ API Staff BP 08714 BP-00012118 P-rograr:t Status on t1TBE ll.ttactnnent I ''lTPE, rreth;l-.1_-butyl ctLer, s )einq :nanufa::tured for us~ as an cr:t.3::-JE' enhancer in notor fue s ))' a nu::tber of companies. A ~:-c":jTcr:> of to:c.col )qical eva ua:.ion of ~1TBE was begun in 1980 by 3 q t::)I.:P of s :_x Ane 1~ lean cornp.o;ni~S .::me one Cerman producer un<ier the 3cspices of th~ API. 7hc p~ogram consists of a 9-dav ~r.Lalation tox~clt/ stuc:y, a tw)-SpEci..es teratology stud~' an<i a slngle-gencrat~on repro~uctic~/~ertLlity study also by - inba la tion, anc1 a pharrnacokir:et Lcs-netabolism study. A 90-day ~ub=hronic inhdlat i.on t0xici t y ;tud}' was dcne by the German Jrn~ucer e~rlier, ln which esse~tially no adverse studies wet:e .,}~.J t='erforrned iild~pendently by participating coMR_anies. 1\. r-=;:>crt of ~:he 9-.jay ir.halat io 1 probe has been received from Bio/dynamics. Exp<:,sures were 0, 100, 300, and 3000 ppm. A. r-educed response to auditory stLmuli and lassitude was observed in the rats exposed to 3000 ppm, indi=ating some central nervous syste~ depression. Liver weigh~s, t~th absolute and relative, ..ere also observed, but there w~re no definitive histopathological :hanges. 'I'he no effect leveJ w.1s det~rmined to be above 300 ppm. Exp-::Jsures for th<"! t:wa-s:pecie~; t!ratcd:Jgy study were completed in 3eptember 1981. A single gener.ttion reproduction study was .~orepleted in early 1982. No sirnific3.nt effects were obse.ored on fertility, fetal d>'!velo;Jrnent, o pup survival. t-tTBE is therefore 10t =en side red rnaternall y to;-:ic embr ]TO toxic, or terat.ogenic. rhE' actual test: exc:JOsur.;:s in th.!se ~:t11dies were approximately 300 ::~pn, 1200 ppn, a.:1.d 3000 ppm, and arE' 20 percent above the target . :cn~entrations. Bi.o/dy~amics, -:he ccntract::>r, reportedsome !Xp~rirnental e~rors that caused these excursions. The audit of thE terato.logy and reprc.duction repcrts by Tracor Jitco, the ~u2l i ty assurance .::ontr.:;ctor, a:1d by ..\PI revealed some inconsisten=ies which will be ccrrected in t~e final report. !'he oharmacokineti-:;s ..,ode shows that. elimina.tion of l-tTBE is ~pparently biphasic, with plasm.1 elimination half lives of 7 1ours and 23 hours, respecti'l:el'' The major route of elimination -~f an i.p. dose- is by expirat.ion; from 70 to 90 percent of the :ipf:lied dose was trapped in tol11ene ?~bblers. Less tha-n 10 :)ercent of the dose was detected as ly small degree of metabolism. Less thCa0n2 , 5 indicating a percent is rel,ativeexcreted- in urine and feces. The highes~ amounts of tissue radioactivity Nere in the liver and kidneys. Met~bolite identification and .JUantification was performed on plasma, kidney, and liver tissues. rormic acid was the rnajcr metabnlite in pooled urine and feces sar.,ples. ll.. final report of ::tll work performed at Bio(Dynamics is anticipatec by March 1, 1984. No additional .testing or research is ~lanned at this tiMe. ~p 08715 BP-00012119